The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment

Dabrafenib

150 mg (PO)

TWICE a day (morning and night) at least one hour before, or at least two hours after a meal

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment

Dabrafenib

150 mg (PO)

TWICE a day (morning and night) at least one hour before, or at least two hours after a meal

No antiemetics should be routinely administered before treatment in patients without a history of nausea and vomiting. If patients experience nausea and/or vomiting, consider using the low antiemetic prophylaxis regimen.

Dabrafenib may prolong the QT interval and increase the risk of cardiac arrhythmia.
Use with caution in patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking medications that may prolong the QT interval, and those with electrolyte disturbances.

Risk factors (e.g. electrolyte abnormalities) should be corrected, where possible, prior to commencement of dabrafenib and the concurrent use of drugs that may prolong the QT interval should be avoided.

Periodic monitoring with ECGs and electrolytes (magnesium, potassium, calcium) should be considered in patients at risk of QT prolongation.

It is important that patients are educated about the prodrome of fever and to cease dabrafenib upon symptom onset. Early intervention results in prompt resolution of events, usually within 24 hours of dose interruption. Paracetamol and NSAIDs may alleviate symptoms during pyrexia.

A septic work-up is not required for patients with uncomplicated pyrexia and without localizing infective symptoms.

In cases of recurrent or severe pyrexia, an intermittent dosing regimen, and/or corticosteroids (prednisolone 10 to 25 mg daily) may be useful. Unlike other toxicities such as fatigue, dose reduction does not appear to reduce the risk of pyrexia recurrence and is best avoided.

BRAF inhibitors appear to be radiosensitising with excess toxicity when given with concurrent radiotherapy. Treatment should be withheld during radiotherapy, however concurrent stereotactic radiotherapy to brain metastases can be provided with minimal additional toxicity.

Dabrafenib has been associated with new primary non-cutaneous malignancies (e.g. colon and adenocarcinoma pancreatic cancer). Patients should be closely monitored for signs and symptoms during therapy and for up to 6 months after discontinuation of dabrafenib or until initiation of another antineoplastic therapy. Refer to dose modifications for more information.

Ocular toxicity

Patients should be routinely monitored for signs and symptoms of uveitis (e.g. blurred vision, photophobia, eye redness and pain). Steroid and mydriatic eye drops may be required to manage uveitis.

Fatigue

Profound fatigue is rare but has been reported in patients especially those with multiple brain metastases.

Dose reduction has shown to be effective, refer to dose modifications for more information.

Blood tests

FBC, EUC, LFTs, calcium and magnesium at baseline. Repeat monthly during treatment, or as clinically indicated. LFTs may become abnormal in the setting of drug-induced fever, and treatment should be withheld until they normalise. INR as clinically indicated.

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

There is limited evidence that indicates dose reductions of dabrafenib reduce the frequency of fever.r If further episodes of fever occur, consider indefinite maintenance prednisolone and/or an intermittent dosing regimen. Dose reductions of dabrafenib to 100 mg twice a day (or as low as 50 mg twice a day) can be considered if clinically indicated.

2nd occurrence: Management as for the first occurrence of rash but commence oral prednisolone 10 mg/day with topical corticosteroids (e.g. mometasone, betamethasone) if not already implemented. When resolved to Grade 1 or less, restart dabrafenib at 150 mg twice a day with prednisolone cover for 1 to 2 weeks or as clinically indicated. Consider dermatology review.

Grade 3

1st occurrence: Management as for Grade 1 rash but stop dabrafenib until resolved to Grade 1 or less, and commence oral prednisolone 10 to 20 mg/day with topical corticosteroids (e.g. mometasone, betamethasone). When resolved, restart dabrafenib at 150 mg twice a day with prednisolone cover for 1 to 2 weeks or as clinically indicated. Consider dermatology review.

2nd occurrence: Management as for the first occurrence of rash. When resolved, restart dabrafenib at 100 mg twice a day with prednisolone cover for 1 to 2 weeks or as clinically indicated. Consider dermatology review.

Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose as follows:
1st occurrence: Reduce dabrafenib to 100 mg twice a day
2nd occurrence: Reduce dabrafenib to 75 mg twice a day
3rd occurrence: Reduce dabrafenib to 50 mg twice a day
4th occurrence: Cease dabrafenib

Discharge information

Dabrafenib capsules

Patient information

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Early (onset days to weeks)

Fever

Non-infectious febrile events are common with BRAF/MEK inhibitors and may occur at any time. Educating patients about the prodrome of fever and drug cessation is an important step in managing the fever.

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation.

Skin toxicities including secondary cutaneous malignancies, hyperkeratosis and maculo-papular rash are associated with dabrafenib and vemurafenib. When treatment is combined with a MEK inhibitor (trametinib or cobimetinib respectively), the prevalence of these toxicities is reduced.

The evidence supporting this protocol is provided by a phase III multicentre international randomised trial (BREAK-III) involving 250 patients comparing dabrafenib with dacarbazine alone in patients with unresectable stage III and IV metastatic melanoma with a BRAF V600E mutation.r

Exclusion criteria included surgery, radiotherapy, or immunotherapy within 4 weeks and previous malignancy within the past 5 years. Patients with CNS metastases were excluded unless they were without evidence of active CNS metastases for more than 3 months after surgery or stereotactic radiosurgery.

The primary end point was progression free survival and secondary end points included overall survival, objective response rate, duration of response, safety and tolerability.r

Efficacy

The estimated median progression-free survival (by independent review) for the dabrafenib group was 6.7 months and 2.9 months for the dacarbazine group (HR=0.35; CI 95% 0.20 to 0.61 ; p<0.0001) with median follow-up of 4.9 months. Patients who had progressed on dacarbazine were permitted to cross over to dabrafenib. The estimated overall survival for the dabrafenib group was 18.2 months versus 15.6 months for the dacarbazine group (HR=0.76; CI 95% 0.48 to 1.21). The 5-year progression-free survival was 12% for the dabrafenib group and 3% for the dacarbazine group. The 5-year overall survival was 24% and 22% respectively.r

Response rates were 49.7% for dabrafenib and 6.3% for dacarbazine.

Non-randomised studies have shown that dabrafenib has activity in patients with brain metastasesrand in melanomas with non-V600E mutations.rr

Toxicity

In patients receiving dabrafenib, the most common adverse events were cutaneous (hyperkeratosis, papillomas, palmar-plantar erythrodysaesthesia), pyrexia, fatigue, headache, and arthralgia. Grade 3-4 adverse events were observed in approximately 33% of patients.r

In 12 patients keratoacanthoma or squamous-cell carcinoma of the skin were observed, which did not require dose modification or interruption. Another 4 patients had basal-cell carcinomas of the skin and one grade 1 mycosis fungoides were observed. Dose reduction of dabrafenib was needed in 52 (28%) patients, and five (3%) patients discontinued drug because of adverse events. One patient died of myocardial infarction/acute coronary syndrome, which was possibly related to dabrafenib.r

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Reviewed at Medical Oncology Reference Committee on 08/04/2016. Nil changes. Next review in 2 years.

31/05/2017

Transferred to new eviQ website.

15/06/2017

Information regarding new primary malignancies that was previously in monitoring section transferred to clinical information in new eviQ website.

15/06/2018

Protocol reviewed at Medical Oncology Reference Committee meeting 15/06/2018. Evidence updated to include 5 year PFS and OS data.
Group consensus to supersede protocol due to superior alternatives being available . Version number changed to V.4. Next review in 2 years.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au